1. Field of the Invention
The invention is relative to a process for purifying 1-[N.sup.2 -((S)-ethoxycarbonyl)-3-phenylpropyl)-N.sup.6 -trifluoroacetyl]-1-lysyl-1-proline (compound I) by extraction and crystallization. ##STR1##
2. Background Information
N-substituted amino acids of this type are valuable intermediates for the production of inhibitors of the angiotensin converting enzyme (ACE), which act as blood-pressure regulators. Compound I is the direct intermediate product for 1-[N.sup.2 -((S)-carboxyl)-3-phenylpropyl)]-L-lysyl-L-proline (lisinopril) compound II, which displays excellent therapeutic results in the combatting of high blood pressure (Zerstril.RTM., Coric.RTM., prinivil.RTM.).
Compound I is obtained according to the state of the art by the reductive amination of 2-oxo-4-phenyl-ethyl butyrate with the dipeptide Lys(Tfa)Pro. ##STR2## Such a process is described in J. Org. Chem. 1988, 53, 836-844. According to this passage, compound I is obtained in a yield of 42% by basic extraction of the raw reaction solution, a subsequent extraction of the product into an organic solvent at pH 4.6 and succeeding crystallization from methyl-tert.butyl ether, cyclohexane.
DE-OS 41 23 248 is relative to the synthesis of compound I, which is obtained according to example 3 in a yield of 60%. The workup of the raw reaction solution obtained according to this process includes, in addition to a basic and an acidic extraction step, a crystallization from methyl-tert.butyl ether. Other processes for producing compound I are also known which are not based on reductive amination but are less advantageous (EP 0,336,368 A2).
However, the basic extraction--an extraction of the aqueous product phase is necessary in order to remove impurities out of the amination reaction --is always associated with product losses by amide- and/or ester splitting of compound I to compound II and of compound I to compounds III and IV. ##STR3##
In order to minimize these product losses, the work must be performed at pH's precisely adjusted, at low temperatures, and with the shortest possible contact times. This is complicated and produces problems, especially on an industrial scale.
The crystallization from methyl-tert.butyl ether is therefore associated with high yield losses since the crystallization must be carried out in high dilution in order to be able to directly obtain the diastereomerically pure compound (I), which reduces the yield. If (I) is allowed to crystallize from solutions with high concentration, an additional recrystallization is necessary. The addition of cyclohexane (J. Org. Chem., 1988, 53, 836-844) during the crystallization is also described for raising the yield. However, there is the danger here of a separation of the product as oil, which makes it much more difficult to isolate the product, not only on an industrial scale.